Mechanisms underpinning meiotic spindle formation and behavior
减数分裂纺锤体形成和行为的基础机制
基本信息
- 批准号:10274040
- 负责人:
- 金额:$ 37.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAneuploidyBehaviorBiochemicalBiological ModelsBipolar ICell divisionCellsCentriolesCentrosomeChromosome SegregationDataDevelopmentDown SyndromeEnsureEventF-ActinFemaleFluorescenceFoundationsGeneticGenomeGerm CellsGoalsHaploidyImageInfertilityKnowledgeLasersLeadLightMaintenanceMediatingMeiosisMicrotubule-Organizing CenterMicrotubulesMitoticMolecularMusOocytesPeripheralPositioning AttributeProcessProteinsPublic HealthRegulationReporterSpontaneous abortionTransgenic Micedevelopmental diseaseeggmalemigrationmouse modelnovelspatiotemporalsperm cell
项目摘要
Project summary
Meiosis is a specialized set of cell divisions that produce haploid gametes. During meiosis I (MI) in females,
bipolar spindle formation and positioning within the oocyte must be regulated tightly to ensure faithful
chromosome segregation and proper genome inheritance. In somatic mitotic cells, bipolar spindle formation
and positioning rely on a centrosome pair, each of which contains two centrioles. Interestingly, meiotic oocytes
lack centrioles and, hence, lack classic centrosomes. Meiotic oocytes, instead, contain numerous microtubule
(MT) organizing centers (MTOCs) that are organized, by largely unknown mechanisms, to establish two
spindle poles (polar MTOCs). The traditional view was that, in mammalian oocytes, MTs (and their associated
proteins) are the only cytoskeletal components responsible for organizing such MTOC spindles. However,
recent data suggest that F-actin is also involved in spindle bipolarity regulation. How F-actin interacts with MTs
to regulate polar MTOC organization during MI represents a critical gap in our understanding of how the
meiotic spindle is built. We recently identified a novel, functionally different, class of MTOCs (mcMTOCs) and
found that spindle maintenance at the oocyte center is regulated by two opposing forces (mcMTOC-mediated
MTs vs. F-actin). We also recently observed that ~50% of spindles are not assembled centrally. To date, such
peripheral spindle assembly was unobservable owing to technical limitations associated with spindle
fluorescence (i.e. live imaging). To circumvent this, we generated a Cep192-eGfp reporter mouse model
enabling spindle tracking wherever it is assembled. Strikingly, peripheral spindle formation is typically followed
by spindle migration towards the center – a previously undocumented phenomenon. Understanding the
molecular mechanisms regulating this corrective developmental event represents a major gap in our
knowledge of meiotic spindle spatiotemporal regulation during MI. This proposal lays the foundations for our
long-term goal: To understand how two critical events during MI — bipolar spindle assembly and positioning —
are regulated, in the absence of centrioles, to ensure faithful chromosome segregation. To do so, we will utilize
state-of-the-art approaches, including transgenic mouse models, genetic constructs, laser ablation, and
cutting-edge imaging, to tackle three critical goals: (i) determine how F-actin interacts with MTs to organize
polar MTOCs during bipolar spindle building, (ii) establish the mechanism(s) by which the peripheral
acentriolar spindle migrates to the oocyte center, and (iii) determine whether differences in biochemical
compositions of mcMTOCs vs. polar MTOCs underlie their functional differences. Given that chromosome
segregation errors (very common during MI) lead to aneuploidy, the leading genetic cause of developmental
disorders and miscarriage, these studies have the potential to significantly advance our basic understanding of
two fundamental processes — spindle formation and positioning — during MI whilst simultaneously shedding
light on why MI is notoriously error prone.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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AHMED BALBOULA其他文献
AHMED BALBOULA的其他文献
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{{ truncateString('AHMED BALBOULA', 18)}}的其他基金
Comparative analysis of molecular events in mammalian oocytes
哺乳动物卵母细胞分子事件的比较分析
- 批准号:
10755189 - 财政年份:2023
- 资助金额:
$ 37.66万 - 项目类别:
Mechanisms underpinning meiotic spindle formation and behavior
减数分裂纺锤体形成和行为的基础机制
- 批准号:
10468208 - 财政年份:2021
- 资助金额:
$ 37.66万 - 项目类别:
Mechanisms underpinning meiotic spindle formation and behavior
减数分裂纺锤体形成和行为的基础机制
- 批准号:
10693863 - 财政年份:2021
- 资助金额:
$ 37.66万 - 项目类别:
Mechanisms underpinning meiotic spindle formation and behavior
减数分裂纺锤体形成和行为的基础机制
- 批准号:
10581903 - 财政年份:2021
- 资助金额:
$ 37.66万 - 项目类别:
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